Accumulation of mutations in antibody and CD8 T cell epitopes in a B cell depleted lymphoma patient with chronic SARS-CoV-2 infection

Khatamzas, E., Antwerpen, M. H., Rehn, A., Graf, A., Hellmuth, J. C., Hollaus, A., Mohr, A. W., Gaitzsch, E., Weiglein, T., Georgi, E., Scherer, C., Stecher, S. S., Gruetzner, S., Blum, H., Krebs, S., Reischer, A., Leutbecher, A., Subklewe, M., Dick, A., Zange, S., Girl, P., Müller, K., Weigert, O., Hopfner, K. P., Stemmler, H. J., von Bergwelt-Baildon, M., Keppler, O. T., Wölfel, R., Muenchhoff, M., Moosmann, A. (2022). Nat Commun 13, 5586.



Antibodies against the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can drive adaptive evolution in immunocompromised patients with chronic infection. Here we longitudinally analyze SARS-CoV-2 sequences in a B cell-depleted, lymphoma patient with chronic, ultimately fatal infection, and identify three mutations in the spike protein that dampen convalescent plasma-mediated neutralization of SARS-CoV-2. Additionally, four mutations emerge in non-spike regions encoding three CD8 T cell epitopes, including one nucleoprotein epitope affected by two mutations. Recognition of each mutant peptide by CD8 T cells from convalescent donors is reduced compared to its ancestral peptide, with additive effects resulting from double mutations. Querying public SARS-CoV-2 sequences shows that these mutations have independently emerged as homoplasies in circulating lineages. Our data thus suggest that potential impacts of CD8 T cells on SARS-CoV-2 mutations, at least in those with humoral immunodeficiency, warrant further investigation to inform on vaccine design.